The role of cellular factors in modulation of entry by ovine betaretroviruses and murine gammaretroviruses

The ability of a virus to infect a host necessarily requires that the virus specifically recognize susceptible target cells. Host cell recognition is mediated by viral proteins, and can involve a wide range of lipid, carbohydrate and protein structures on the target cells. The work presented here examines in detail the factors that modulate recognition of host cells by members of the family retroviridae. We have investigated the mechanism of non-reciprocal interference observed between xenotropic and polytropic murine leukemia viruses. We find that two virus receptors are simultaneously present in different domains of the cellular protein XPR1, and that these receptors are variably used by xenotropic and polytropic viruses.; We have also investigated the involvement of host cell factors in addition to the primary receptor Hyal2 in the entry of Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV). In the case of ENTV, we have shown that expression of the human Hyal2 protein allows only low level infection in cells derived from rats. Biochemical studies confirm that the Hyal2 protein is expressed at high levels on rat cells, and the expressed protein binds ENTV envelope. Additional co-culture and somatic cell hybrid experiments suggests that ENTV requires an entry co-factor that is lacking in cells derived from rats.; In a final series of experiments, we have identified the RON receptor tyrosine kinase as a specific inhibitor of JSRV Env mediated entry. We find that expression of RON in multiple cell lines results in a specific decrease in JSRV Env mediated entry. We have investigated the mechanism of RON mediated inhibition, and find that RON does not block binding of JSRV Env to Hyal2. Furthermore, RON does not inhibit the uptake of JSRV pseudotype particles from the cell surface. These results are consistent with a novel mechanism whereby RON expression prevents fusion by the JSRV envelope. In summary, our studies have identified a number of cellular factors that modulate the entry of different retroviruses, and demonstrate that interactions of these viruses with target cells involve a complex series of interactions between both required and inhibitory factors.